The platelet integrin alpha-IIb-beta3 mediates platelet aggregation and plays a critical role in hemostasis. Patients without functional alphaIIb-beta3 receptors manifest in the bleeding disorder Glanzmann thrombasthenia (GT). The medical importance of alphalIb-beta3 is highlighted, by the ability of alphalIb-beta3 antagonists to prevent the ischemic complications of unstable angina and percutaneous coronary interventions. Some mutations in the alphalIb submit that result in GT have been shown to completely block maturational processing of alphalIb, causing the protein to be retained in the endoplasmic reticulum (ER). In particular, mutations in and around the four cation-binding domains of alpha1Ib universally result in ER retention. These specific cases of GT comprise a paradigm for agenetic disease caused by a conformational change in protein structure which results in abnormal ER processing, and ultimately results in ER retention and degradation. The alpha1Ib cation-binding domains have highly conserved hydrophobic residues that are required for the normal biogenesis of the receptor complex. Even conservative amino acid substitutions in these regions profoundly affects the level of alpha1Ib expression and degree of maturation. These data suggest that the conservative changes in the cation-binding domains are altering their structure, which affects their cation binding affinity. That these changes result in ERAD suggest that calcium binding to the cation-binding domains is essential for normal ER processing of alpha1Ib. This hypothesis will be tested by the following specific aims: (1) To test the hypothesis that normal maturation of the alpha1Ib subunit requires structurally intact cation binding domains. (2) To test the hypothesis that normal biogenesis of the alpha1Ib-beta3 receptor complex requires calcium binding to the alpha1lb cation-binding domains. (3) To identify ER chaperones that interact with alpha1Ib, and to test the hypothesis that calcium binding to the alpha1Ib cation-binding, affects interaction with chaperone proteins.